Etravirine (“ETV”), 4-(6-amino-5-bromo-2-(4-cyanophenylamino)pyrimidin-4-yloxy)-3,5-dimethylbenzonitrile of the following chemical structure:
is a drug used for the treatment of HIV.
Etravirine is formerly known as TMC-125, brand name Intelence®.
Etravirine, its analogs and their synthesis are described in U.S. Pat. No. 7,037,917. In this patent Etravirine is prepared by reacting a tetrahoganated pyrimidine derivative and aminobenzene derivative, and optionally brominating the obtained compound, to obtain Etravirine. This process includes two steps of chromatographic purification of Etravirine's intermediates, and the final product is obtained in very poor overall yield.
EP 945443 claims a general process for the preparation of anilinopyrimidine derivatives, and salts thereof, e.g., by aminolysis reactions of pyrimidine compounds containing leaving groups.
Bioorg. Med. Chem. Lett. 11 (2001) 2235-2239 describes a process for preparing Etravirine, according to the following scheme:
where Etravirine is obtained in a very poor overall yield of less than 10%.
WO 01/85700 describes preparation of Etravirine analogues, which do not include an NH2 group. In this process, Etravirine analogues are also purified by column chromatography and are obtained in very poor overall yield of about 2-5%.
WO 2006/094930, WO 2008/071587 and WO 2000/027825 describe different processes for preparation of different Etravirine intermediates and derivatives, all of which require at least one chromatographic purification step.
WO 2008/068299 discloses that Etravirine has very poor solubility in water, and describes a hydrobromide salt of Etravirine, which is prepared by dissolving Etravirine in dichloromethane and reacting with hydrobromic acid.
The present invention addresses the need to obtain debrometravirine (“DEBETV”) and Etravirine in high yield and purity, in a method that can be adapted to industrial scale. The present invention provides a new synthesis of Etravirine, via a novel intermediate, 4-(2,6-dichloropyrimidin-4-yloxy)-3,5-dimethylbenzonitrile (“ETHER”). Also described are purification processes for DEBETV and Etravirine.